Microbubble-Templated Immunoactive Metal-Phenolic Capsules for Drug Delivery and Enhanced Cancer Immunotherapy

Advanced drug delivery systems integrating immunomodulatory functions can improve cancer therapy. Herein, we develop a novel metal-phenolic capsule for synergistic drug delivery and immunomodulation. Specifically, a stable metal-phenolic network (MPN), formed by Fe (III), tannic acid, and catechol-modified hyaluronic acid, was assembled onto doxorubicin (DOX)-loaded mannose-glycated bovine serum albumin microbubbles to construct microcapsules with both drug loading and immunomodulatory functions simultaneously. The capsules release DOX in a pH-responsive manner and induce reactive oxygen species accumulation in tumor cells, thereby enhancing immunogenic cell death (ICD). This ICD effect, combined with the direct stimulation of dendritic cells (DCs) by the capsules and the paracrine signaling from capsule-activated M1 macrophages, synergistically promotes DC maturation. In vivo bilateral tumor models demonstrate that DmTFH substantially inhibits primary and distant tumor development and markedly delays metastasis to the lungs. Flow cytometry analysis confirms robust local and systemic immune responses, characterized by enhanced DC maturation within lymph nodes and increased infiltration of activated CD8⁺ and CD4⁺ T cells in tumors and spleens. Overall, the immunoactive MPN microcapsules constructed in this study enhance the immunotherapeutic efficacy of DOX through the synergistic action of carrier-inherent immunomodulation and chemotherapy, providing a promising approach for combinatorial cancer therapy.